ArticleThe Journal of physiology2012
Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits.
Article in The Journal of physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 77 papers.
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Who cites it
77 citing papers in PubMed, 124 citations in OpenAlex.
- Phase 2 Re-Entry Without IJACC. Clinical electrophysiology · 2023Trial
- Variable expressivity in long QT syndrome type 2 rabbits defines a low threshold for therapeuticAmerican journal of physiology. Heart and circulatory physiology · 2026Article
- Sex-specific virtual population for the prediction and assessment of arrhythmia risk.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2026Article
- Modes of onset of ventricular arrhythmias in J-wave syndromes: mechanistic insights from computational modeling.American journal of physiology. Heart and circulatory physiology · 2026Article
- LQT1 patients have augmented response of repolarization dispersion following atropine induced heart rate increase versus healthy controls.Physiological reports · 2026Article
- Population Modeling Approach for Human Cardiac Arrhythmia Risk Prediction.Circulation. Arrhythmia and electrophysiology · 2026Article
- Methadone Blockade of Inward Rectifier Potassium Current Promotes Both Early and Delayed Repolarization Arrhythmias: Mechanistic Insights From Computational Modeling.Journal of the American Heart Association · 2025Article
- Different beta-blockers for preventing arrhythmic events in patients with long QT syndrome: a network meta-analysis.Frontiers in medicine · 2025Article
- KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome.European heart journal · 2024Article
- From genes to clinical management: A comprehensive review of long QT syndrome pathogenesis and treatment.Heart rhythm O2 · 2024Review
- Management of patients with an electrical storm or clustered ventricular arrhythmias: a clinical consensus statement of the European Heart Rhythm Association of the ESC-endorsed by the Asia-Pacific Heart Rhythm Society, Heart Rhythm Society, and Latin-American Heart Rhythm Society.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2024Article
- E3 ubiquitin ligase rififylin has yin and yang effects on rabbit cardiac transient outward potassium currents (IThe Journal of biological chemistry · 2024Article
- Dissecting the roles of calcium cycling and its coupling with voltage in the genesis of early afterdepolarizations in cardiac myocyte models.PLoS computational biology · 2024Article
- Deciphering the roles of triiodothyronine (T3) and thyroid-stimulating hormone (TSH) on cardiac electrical remodeling in clinical and experimental hypothyroidism.Journal of physiology and biochemistry · 2024Review
- Mechanistic insights into spontaneous transition from cellular alternans to ventricular fibrillation.Physiological reports · 2023Article
- Subcellular Propagation of Cardiomyocyte β-Adrenergic Activation of Calcium Uptake Involves Internal β-Receptors and AKAP7.Function (Oxford, England) · 2022Article
- Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction.The Journal of clinical investigation · 2021Article
- Emerging evidence for a mechanistic link between low-frequency oscillation of ventricular repolarization measured from the electrocardiogram T-wave vector and arrhythmia.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2021Review
- Mechanisms of phase-3 early afterdepolarizations and triggered activities in ventricular myocyte models.Physiological reports · 2021Article
- Long-QT founder variant T309I-Kv7.1 with dominant negative pattern may predispose delayed afterdepolarizations under β-adrenergic stimulation.Scientific reports · 2021Article
17 more citing papers are in PubMed but not listed here.
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Early after-depolarization (EAD), or abnormal depolarization during the plateau phase of action potentials, is a hallmark of long-QT syndrome (LQTS). More than 13 genes have been identified as responsible for LQTS, and elevated risks for EADs may depend on genotypes, such as exercise in LQT1 vs. sudden arousal in LQT2 patients. We investigated mechanisms underlying different high-risk conditions that trigger EADs using transgenic rabbit models of LQT1 and LQT2, which lack I(Ks) and I(Kr) (slow and fast components of delayed rectifying K(+) current), respectively. Single-cell patch-clamp studies show that prolongation of action potential duration (APD) can be further enhanced by lowering extracellular potassium concentration ([K(+)](o)) from 5.4 to 3.6 mm. However, only LQT2 myocytes developed spontaneous EADs following perfusion with lower [K(+)](o), while there was no EAD formation in littermate control (LMC) or LQT1 myocytes, although APDs were also prolonged in LMC myocytes and LQT1 myocytes. Isoprenaline (ISO) prolonged APDs and triggered EADs in LQT1 myocytes in the presence of lower [K(+)](o). In contrast, continuous ISO perfusion diminished APD prolongation and reduced the incidence of EADs in LQT2 myocytes. These different effects of ISO on LQT1 and LQT2 were verified by optical mapping of the whole heart, suggesting that ISO-induced EADs are genotype specific. Further voltage-clamp studies revealed that ISO increases L-type calcium current (I(Ca)) faster than I(Ks) (time constant 9.2 s for I(Ca) and 43.6 s for I(Ks)), and computer simulation demonstrated a high-risk window of EADs in LQT2 during ISO perfusion owing to mismatch in the time courses of I(Ca) and I(Ks), which may explain why a sympathetic surge rather than high sympathetic tone can be an effective trigger of EADs in LQT2 perfused hearts. In summary, EAD formation is genotype specific, such that EADs can be elicited in LQT2 myocytes simply by lowering [K(+)](o), while LQT1 myocytes require sympathetic stimulation. Slower activation of I(Ks) than of I(Ca) by ISO may explain why different sympathetic modes, i.e. sympathetic surge vs. high sympathetic tone, are associated with polymorphic ventricular tachycardia in LQTS patients.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.